Theranostic Nanoprobe Mediated Simultaneous Monitoring and Inhibition of P-Glycoprotein Potentiating Multidrug-Resistant Cancer Therapy

Abstract

Multidrug resistance is a major cause of failure in the clinical cancer therapy, in which the overexpression of P-glycoprotein (P-gp) plays a crucial role. Herein, we fabricate a theranostic nanoprobe with the function of simultaneous detection and inhibition of P-gp to diagnose and combat multidrug-resistant cancer in vitro and in vivo. For constructing the nanoprobe, elacridar modified quantum dots (QDs-Ela), acting as a gatekeeper, are grafted onto the doxorubicin (DOX) loaded, folic acid (FA) decorated mesoporous silica nanoparticles (MSNs). Upon targeted uptake by multidrugresistant cancer cells, Bel-7402/ADR are used as a model, the acidic environment results in QDs-Ela removal from the nanoprobe, and subsequent DOX release. The removed QDs-Ela could specifically combine with P-gp in the cancer cell membrane and inhibit their active sites, which prevents the efflux of intracellular DOX and increases the retention of DOX. Another way, the fluorescence intensity of the binding QDs-Ela quantifies the P-gp expression level. Subsequently, in vitro and in vivo experiments both demonstrate the enhanced multidrug-resistant cancer therapy efficacy, i.e., nanoprobe has 10 times better curative effect than free DOX. In addition, due to the conjugation of FA, the nanoprobe exhibits a selective cell targeting ability to Bel-7402/ADR cells. This nanoplatform paves a new avenue for the accurate treatment of multidrug-resistant cancers.

Activatable Fluorescence Imaging and Targeted Drug Delivery via Extracellular Vesicle-Like Porous Coordination Polymer Nanoparticles

“…Cell membrane (CM) extracted from Bel-7402 cancer cells was then coated on the PCP-DOX to mimic EVs, which have been demonstrated to have the ability of evading phagocytosis and enhancing specific endocytosis by homotypic cells. , After CM coating, the size of NPs further increased to 244 nm (Figure b) and zeta potential turned to −15.4 mV ascribed to the negative charges of CM. To further verify that CM can be successfully encapsulated on the nanoparticle surface, cell membrane dye (DiO) was used to label the CM to avoid the fluorescence interference of DOX; here, CM was coated on the PCP NPs without DOX (PCP-CM), green spots were visualized by CLSM (Figure d), while as a control no fluorescence spots were observed for PCP NPs without CM (Figure S6).…”

“…MTT assay was carried out to investigate the toxicity of prepared material. 28 Bel-7402 cells were first seeded to four 96-well plates at a seeding density of ∼5 × 10 4 cells per well in 200 μL of complete medium, which was incubated at 37 °C for 24 h. After rinsing with PBS, two plates of Bel-7402 cells were incubated with 200 μL of culture media containing different concentrations of PCP-CM, PCP-DOX-CM, and PCP-DOX for 24 h. Another two plates of Bel-7402 cells were incubated with 200 μL of culture media containing 80 μg mL −1 of PCP-CM, PCP-DOX-CM, and PCP-DOX for different time periods. After rinsing with PBS, 50 μL of MTT solution in binding buffer from MTT cell proliferation and cytotoxicity assay kit was added to each well.…”

Design of Targeted Nanostructured Coordination Polymers (NCPs) for Cancer Therapy

“…The reported NCPs were synthesized by the coordination of polyphenol ligands and dopamine with Fe(III) ions. Subsequently, the NCPs were loaded with DOX through physical and electrostatic absorption, and then the nanoparticles were coated with a cell membrane extracted from Bel-7402 cancer cells, which have been demonstrated to afford the ability to evade phagocytosis and enhance specific endocytosis by homotypic cells [98]. The fluorescence of DOX was quenched due to the fluorescence resonance energy transfer between DOX and the coordination polymeric matrix.…”

Approaches to minimize the effects of P‐glycoprotein in drug transport: A review

“…P‐glycoprotein (P‐gp, permeability glycoprotein), also known as ABCB1 (ATP binding cassette sub‐family B member 1) drug transporter, plays a crucial role in the pharmacokinetic profile of drugs (Kopcho et al, 2019; Kopecka et al, 2020; Mareux et al, 2021; Mora Lagares et al, 2019; Wei et al, 2019). Structurally, P‐gp consists of two nucleotide‐binding domains (hydrophilic) and two trans‐membrane binding domains (hydrophobic) (Alam et al, 2019; Dastvan et al, 2019; Leopoldo et al, 2019; Nanayakkara et al, 2018).…”